The human inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, affect over one million Americans and significant unmet medical needs still exist. Activation of NF??B transcription factors are central events in the initiation and perpetuation of chronic inflammation in IBD. TheraLogics, Inc., have been at the forefront of NF??B research and hold intellectual property pertaining to novel NF??B inhibitor peptides including TLX1423. TLX1423 is a peptide comprised of a 8 lysine (8K) protein transduction domain (PTD) with an I?B kinase (IKK) inhibitory sequence, NF??B essential modulator (NEMO) binding domain (NBD). Compared to other NF??B inhibitors, TLX1423 has the advantages of inhibiting activated NF??B, a hallmark of chronic inflammation, but not inhibiting basal NF??B activity, involved in fundamental cellular processes thus correlating with toxicity. During phase 1, we achieved important milestones in the development of TLX1423 as a therapy for IBD and published these findings in the Journal of Immunology. We demonstrated transduction of TLX1423 into cells and tissues. In-vivo, TLX1423 inhibited LPS-activated NF??B in the ileum, but did not inhibit basal NF??B in Peyer's patches. IL-10-/- mice treated systemically with TLX1423 demonstrated amelioration of established colitis and decreased NF??B activation in the lamina propria. In phase 1, we also demonstrated that intrarectal administration of TLX1423 results in amelioration of intestinal inflammation in two experimental IBD models. The ideal therapeutic agent to treat IBD would be administered by mouth. However, drug delivery to the inflamed intestine remains a challenge for two main reasons: 1) lack of highly effective immunomodulatory agents that can be delivered locally and inhibit their targets in intestinal immune cells and, 2) lack of vehicles to carry these agents to the site of inflammation with minimal degradation in the GI tract. The multidisciplinary team assembled for this phase 2 proposal has developed innovative solutions to these hurdles. This would be an important advancement to minimize toxicity, increase patient compliance, and improve quality of life. To address these challenges, we have developed microemulsion (ME)- based delivery systems suitable for local administration of TLX1423, and via enteric release strategies, target the peptide to inflamed regions of the GI tract. We show preliminary data that PTD peptides in water-in-oil (w/o) MEs are efficiently delivered to the large intestine in mice as compared to free PTD peptides. TheraLogics has enlisted CMC, regulatory and clinical consultants to translate results of this phase 2 program into the next phases, including GMP manufacturing, GLP safety/toxicity studies, and an IND submission. PUBLIC HEALTH RELEVANCE: This is an STTR application representing an industry-academic collaboration between TheraLogics, Inc., the University of North Carolina at Chapel Hill, and the North Carolina State School of Veterinary Medicine. The applicant organization is TheraLogics, Inc., a small North Carolina based biotechnology company. The Principal Investigator on this application is Scott E. Plevy in the University of North Carolina School of Medicine. The purpose of this application is to develop a novel NF??B inhibitor for the treatment of inflammatory bowel disease. The investigators have already been successful in demonstrating efficacy of the NF??B inhibitor in experimental models of colitis. This application will further develop this inhibitor for oral delivery and further test this molecule in small and lrge animals. It is our hope that the work performed in this application will lead to clinical development in humans in the next phase.